The aim of this proposal is to develop a novel class of Alzheimer's Disease (AD) therapeutics acting via a hitherto unexplored mechanism of action. AD is the sixth-leading cause of death in the United States with no known cure. The burden on families and caregivers of patients is immense, with the annual cost of care approaching $1 trillion. The exorbitant strain of AD arises, in large part, to the lack of effective, innovative ad disease-modifying treatment options. A prominent pathological feature of AD is a robust activation of the neuronal lysosomal pathway, endocytosis and autophagy - disturbances of which are associated with lysosomal cytotoxicity and represent one of the earliest manifestations in sporadic AD. Furthermore, dysfunction in lysosomal storage and indigestibility of glycosaminoglycans (GAGs) such as heparan sulfate GAGs (HS-GAGs) is also the primary cause of several neurodegenerative diseases known as mucopolysaccharidoses. HS-GAGs interact with key molecules implicated in AD pathogenesis, i.e., -amyloid (Abeta), Tau and Apolipoprotein E. Our biotechnology company has discovered a new series of proprietary compounds called Glycosaminoglycan-Interacting Small Molecule (GISMO). These molecules work via a unique mechanism of action to inhibit protein interactions with HS-GAGs, and as such, represent a novel therapeutic approach for the treatment of AD. The goal of this proposal is to develop a novel AD therapeutic that inhibits uptake of HS-GAG/Abeta protein aggregates via endo-lysosomal route. Consequently, GISMO compounds are expected to prevent lysosomal storage of HS-GAGs (complexed with Abeta) and protect nerve cells against lysosomal dysfunction and cytotoxicity. Furthermore, GISMO compounds may also dissipate already aggregated Abeta bound to GAGs and reduce further accumulation of extracellular Abeta, by dissociating the Abeta-GAG complexes. During this project, Specific Aim 1 is to evaluate 24 already identified lead compounds for in vitro potency and safety; Specific Aim 2 is to perform lead optimization to improve safety and selectivity; and Specific Aim 3 is to assess pharmacokinetic properties of lead compounds to identify brain-penetrant compounds. The successful completion of these studies will result in identification of three optimized lead compounds that will be subjected to in vivo testing in animal models of AD, with the subsequent aim of identifying a Preclinical Candidate for IND-enabling studies.